This application proposes to conduct several timely and cost-efficient blood-based and diet-based studies to expand upon recent randomized trial findings for age-related macular degeneration (AMD) in the Women's Antioxidant Folic Acid Cardiovascular Study (WAFACS). WAFACS was a randomized, double-blind, placebo-controlled trial conducted among female health professionals aged 40 years or older who were at high risk of cardiovascular events. The findings for AMD in WAFACS, based on an average of 7.3 years of treatment and follow-up of 5,205 women in the folic acid arm, indicate a statistically-significant 34% reduced risk of confirmed AMD (55 cases vs. 82 cases) for those assigned to active treatment with folic acid (2.5 mg/d), vitamin B6 (50 mg/d), and vitamin B12 (1 mg/d). Supplementation with folic acid and B vitamins is known to reduce plasma levels of homocysteine. Therefore, a primary aim of this proposal is to address the causal relevance of homocysteine to AMD by conducting the first prospective studies of plasma homocysteine and AMD in women and men utilizing available data from WAFACS, the Women's Health Study, and Physicians' Health Study II. A total of 829 cases of confirmed AMD have been documented among participants with baseline blood specimens in these cohorts and are available for analysis. We will also utilize archived blood specimens collected at baseline and at follow-up for 300 participants in WAFACS to examine the effect of folic acid/B6/B12 supplementation on four biomarkers of inflammation and endothelial dysfunction found to be associated with risks of AMD in observational studies. Finally, we will explore whether the reduced risk of AMD observed in WAFACS reflects the homocysteine-lowering effect of folic acid and B vitamins by utilizing archived blood specimens collected at baseline to contrast the magnitude of risk reduction in women with baseline homocysteine level above, as compared to below, the median value. We will also explore the modifying effect of baseline levels of plasma folate, vitamin B6, and vitamin B12 on the effectiveness of folic acid/B6/B12 supplementation. This proposal represents an extraordinarily cost-efficient opportunity to extend the promising overall findings for AMD in WAFACS to important blood-based and diet-based subgroups. The information derived from these studies will address important gaps in knowledge regarding the homocysteine-AMD hypothesis, and should contribute to the efficient design of future trials in other populations to critically evaluate the possible beneficial effect of folic acid and B vitamin supplementation in AMD.